Synthesis of Platinum Complexes from N-Benzyl-2-Aminoethanethiol Derivatives
Peer-Reviewed Protocol
TheScientificWorldJOURNAL (2003) 3
1537-744X
Synthesis of Platinum Complexes from N-Benzyl- 2-Aminoethanethiol Derivatives
Mauro Vieira de Almeida 1
Laura Lúcia C. de Oliveira 1
Eloi Teixeira Cesar 0
Marcus Vinícius N. de Souza 1
0 Colégio de Aplicação João XXIII, UFJF , 36036-330, Juiz de Fora-MG , Brazil
1 Departamento de Química
Twelve new platinum(II) complexes, analogs of cisplatin, containing a 2aminoethanethiol N-substituted by several benzyl groups have been prepared and characterized in good yields. The ligands were obtained by reaction between 2aminoethanethiol hydrochloride and different benzyl halides.
platinum(II) complexes; N-benzyl-2-aminoethanethiol; anticancer agents; cisplatin
INTRODUCTION
Cisplatin (Fig. 1) is an important drug in the fight against cancer. In association with other types
of drugs, it is highly effective in the treatment of different kinds of neoplasias[1,2,3]. The
biological activity of cisplatin was discovered by Rosenberg et al. at the end of the 1960s[4]. Due
to its side effects, the appearance of resistance, and low solubility[5,6,7], new platinum
complexes have been synthesized such as carboplatin, oxaliplatin, and nedaplatin (Fig. 1).
Carboplatin shows the same level of activity as cisplatin in the treatment of some kinds of cancer
and is much less nephrotoxic and emetic[8]. Oxaliplatin has been approved for the treatment of
colorectal cancer in France, and nedaplatin has received approval for use in Japan. Oxaliplatin
and nedaplatin have yet to demonstrate significant advantages over cisplatin or carboplatin[9].
This fact shows how it is important to develop new platinum complexes that could effectively act
in a larger number of tumors. At the same time, those complexes should present less severe side
effects and they should be active in resistant cells lines.
Since some substituted ethylenediamine platinum complexes have shown antitumor activity
against a variety of cell tumors[10,11], and also aromatic compounds have shown the possibility
of intercalation between DNA bases[12], we synthesized complexes containing a platinum center
bound to ethylenediamine derivatives that demonstrated cytotoxicity in vitro in carcinoma buccal
human cells[13]. Based on those results, we decided to synthesize platinum(II) complexes
*Corresponding author.
©2003 with author.
containing 2-aminoethanethiol N-substituted with several benzyl groups. This choice was made
because of the close structural similarity among 2-aminoethanethiol, ethylenediamine, and
cysteine.
Cl
Cl
Pt
Cisplatin
NH3
NH3
O
O
O
O
P t
Carboplatin
NH3
NH3
H2
N
Pt
N
H2
Oxaliplatin
O
O
O
O
H3N
H3N
O
O
P t
Nedaplatin O
RESULTS AND DISCUSSION
The ligands 6–10 were prepared in satisfactory yields (50–100%) by the reaction of
2aminoethanethiol hydrochloride and sodium bicarbonate with the corresponding benzyl halide 1-5
in ethanol, in a range varying between 70 h to 7 days (Scheme 1). 1H NMR of the ligands showed
signals between δ 2.6–2.7, 3.0–3.1, 3.6–3.9, and 7.1–8.4 corresponding to the CH2SH, CH2NH,
benzyl CH2 and the aromatic hydrogens, respectively. In the 1H NMR spectrum of compound 9, a
signal at δ 3.67, attributable to the OCH3, was also noticed. 13C NMR spectra showed signals
between δ 28.0–35.0, 34.4–35.4, 38.5–39.4, and 114.1–159.2, corresponding to the methylenic
carbons CH2SH, CH2NH, benzyl CH2, and aromatic carbons. Furthermore, a signal at δ 55.1
attributable to the OCH3 of compound 9 was also found. The IR spectra of these ligands showed
absorptions corresponding to aromatic CH, NH, and SH at 3033–2907, 2950–3065, and 2550–
2588 cm-1, respectively. For compounds 8 and 10, absorptions attributable to NO2 at 1509, 1245
cm-1 and 1450, 1347 cm-1 were also noticed.
The dichloro platinum(II) complexes 11–15 (65–88% yield) were synthesized by the reaction
of these ligands with K2[PtCl4] in water at room temperature for 24 h and isolated by filtration.
For the complexes, one can see in their IR spectra absorptions corresponding to γ Pt-N, γ Pt-S,
and γ Pt-Cl between 500–550, 440–476, and 300–338 cm-1, respectively, in addition to the
absorptions observed for the ligands. In the 1H NMR spectrum of these complexes, signals were
observed between δ 2.1–2.8 and 3.0–3.1, corresponding to the CH2SH and CH2NH, signals
between δ 4.0–4.8 in the case of benzyl CH2, and finally signals in the region of δ 7.1–8.2 for the
aromatic hydrogens. The compound 14 also showed a signal at δ 3.8 attributable to the OCH3.
The compounds 6–10 were reacted with an equimolar amount of in situ generated
potassium tetraiodoplatinate(II) to produce diiodo platinum(II) complexes 16–20, in 89–100%
yields. Besides the absorptions observed in the spectra of the ligands, the IR spectra of the iodine
complexes 16–20 showed γ Pt-N and γ Pt-S between 527–547 and 435–468 cm-1, respectively. 1H
NMR spectra of these complexes showed signals between δ 2.4–2.7, 2.7–3.3, 4.3–4.8, and 7.0–
8.8 corresponding to t (...truncated)